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oai:repisalud.isciii.es:20.500.12105/76622024-09-27T08:43:38Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Fuster, Jose J. author Molina-Sanchez, Pedro author Jovaní, David author Vinué, Ángela author Serrano, Manuel author Andres, Vicente author 2012-03 RATIONALE: Human genome-wide association studies have identified genetic variants in the chromosome 9p21 region that confer increased risk of coronary artery disease and other age-related diseases. These variants are located in a block of high linkage disequilibrium with the neighboring Ink4/Arf tumor-suppressor locus (also named CDKN2A/CDKN2B). Since previous studies suggest an atheroprotective role of the Ink4/Arf locus, here we assessed whether gain-of-function of the encoded genes can be exploited therapeutically to reduce atherosclerosis. METHODS: Generation and characterization of apolipoprotein E-null mice carrying an additional transgenic copy of the entire Ink4/Arf locus (apoE-/-Super-Ink4/Arf) that reproduces the normal expression and regulation of the endogenous locus. RESULTS: Although liver and aorta of apoE-/-Super-Ink4/Arf mice only showed a trend towards increased Ink4/Arf transcript levels compared to apoE-/- controls, cultured macrophages with increased Ink4/Arf gene dosage exhibited augmented apoptosis induced by irradiation with ultraviolet light, indicating that low level of transgene overexpression can lead to augmented Ink4/Arf function. However, increased Ink4/Arf gene dosage did not affect atherosclerosis development in different vascular regions of both male and female apoE-/- mice fed either normal or high-fat diet. Increased gene dosage of Ink4/Arf similarly had no effect on atheroma cell composition or collagen content, an index of plaque stability. CONCLUSION: In contrast with previous studies demonstrating cancer resistance in Super-Ink4/Arf mice carrying an additional transgenic copy of the entire Ink4/Arf locus, our results cast doubt on the potential of Ink4/Arf activation as a strategy for the treatment of atherosclerotic disease. Atherosclerosis. 2012; 221(1):98-105 10.1016/j.atherosclerosis.2011.12.013 1879-1484 0021-9150 Atherosclerosis 22226369 http://hdl.handle.net/20.500.12105/7662 Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice